This application requests funding for a mentored predoctoral training program involving the use of psychoneuroendocrine research methods to better understand sex differences in schizophrenia. The general aim of the proposed research training program is to identify neuroendocrine mechanisms that contribute to variations in cognitive function in schizophrenia. The specific aims of the research are to characterize how individual variation in estrogen levels affects cognitive abilities that show a sex difference. The longer-term objective of the research program will be to apply didactic training in psychoneuroendocrinology and hands-on research training to the systematic investigation of sex differences in schizophrenia. Women with schizophrenia have decreased levels of estrogen, and variations in estrogen affects cognitive processes (e.g., verbal memory, visuospatial abilities) that are impaired in the disease. In the proposed study we will examine the effects of endogenous estrogen on cognition in schizophrenia using a non-invasive menstrual cycle paradigm. Sixty normally cycling women (30 healthy and 30 patients) will complete a battery of neuropsychological tests at two points in the menstrual cycle. Testing will occur at the early follicular (low estrogen and progesterone; days 2-4) phase and the midluteal (high hormones; days 21- 25) phase. Time between testing will be approximately 1.5-months (i.e., during two separate cycles). We will also examine cognitive function in 30 men with and 30 without schizophrenia at two points in time, at the first session and 1.5-months later. We hypothesize that women with schizophrenia will show improvements in clinical symptoms, visual scanning, and fine motor skills and perform worse on visuospatial abilities when estrogen levels are high compared to low levels of estrogen, and that these changes will correlate with changes in estradiol. Conversely, we predict that verbal abilities, including verbal fluency and verbal memory, will decrease during the midluteal compared to early follicular phase, and that these effects will correlate with changes in progesterone. These results will lay the foundation for a larger research program in this area by establishing sex differences in sexually dimorphic cognitive abilities (abilities where men or women show an advantage) in schizophrenia, and by demonstrating that deficits in these domains vary with endogenous hormone levels over the menstrual cycle. This new line of work can provide new insights into the potential modulatory effects of estrogen and progesterone in mediating symptoms and cognition in schizophrenia, and guide development of novel endocrine interventions to reduce the treatment resistant cognitive impairments that are a major cause of disability in schizophrenia. [unreadable] [unreadable] [unreadable]